Estrogen receptor (ER) regulates transcription in conjunction with the action of coregulatory moleculesthat interact with the receptor in a ligand-dependent fashion. The gene for one of these ER coregulators,AIB1, is amplified in a subset of human breast cancers and functions as an oncogene. Work from severallabs including our own have implicated AIB1 and other coregulatorsin determiningthe tissue and tumor-specific activities of selective estrogen receptor modulators (SEiRMs) such as tamoxifen and as playing a role in tamoxifen resistance. Aromatase inhibitors(Al) have replaced tamoxifenas first-line endocrinetherapy for post-menopausal women with advanced ER+ breast cancer and are rapidly replacing tamoxifen in early stage ER+ breast cancer as well. However, little is known concerning the mechanism underlyingde novo resistance to Al therapy. We hypothesize that the levels and activity of A1B1 and other ER coregulatorsplay a role in determining a tumor's response to Al therapy. We will test this hypothesis in cell-based models of estrogen deprivation, a transgenic mouse model of A1B1-dependent breast cancer, and in the pre-surgical setting in postmenopausal women with newly diagnosed ER+ breast cancer. These studies will facilitate the translation of progress in our basic understanding of the importance of coregulators in ER action to improvements in endocrine therapy.